DESCRIPTION: (Applicant's Abstract) Our promising research in healthy human volunteers has provided preliminary evidence that isradipine, a dihydropyridine-class calcium channel antagonist (DCCCA), significantly reduces the rewarding (including euphoric) effects of methamphetamine mediating its abuse potential. This proposal aims to determine if these anti-rewarding effects of isradipine will generalize to methamphetamine dependent individuals during drug-taking, thereby laying the foundation for the programmatic development of DCCCA in future clinical trials as treatment agents for methamphetamine dependence. Using state-of-the-art measures of human liability assessment, we plan to conduct two placebo-controlled, double-blind studies using a counter-balanced (for sequence and ordinal position) cross-over design in which we will examine the behavioral and physiological effects of d-methamphetamine both alone and in combination with isradipine. Subjects will be forty-two non treatment-seeking methamphetamine dependent men and women. Experiment #1, a proof-of-concept analysis, will test the hypothesis that acute isradipine pretreatment reduces methamphetamine-induced changes in subjective mood and other measures of human abuse liability. Secondarily, we will determine, if and by how much, d-methamphetamine-induced changes in cognitive, psychomotor, and physiological function, are altered by isradipine in non-fatigued subjects during drug-taking. Experiment #2 addresses issues of potential clinical effectiveness and utility by testing the hypothesis that repeated isradipine administration will: a) antagonize d-methamphetamine's rewarding effects, and b) prove to be clinically tolerable by decreasing d-methamphetamine's pressor effects while producing no cognitive or psychomotor deterioration. Establishing isradipine's effectiveness and tolerability in the human laboratory lays a solid foundation for its use in future clinical trials for the treatment of methamphetamine dependence. This study supports NIDA's mission to develop effective medications for the treatment of methamphetamine dependence, and to understand the pharmaco-behavioral processes associated with psychostimulant use.